The present invention relates to processes of making a crystalline form of 7-[4-[4-(2,3-dichlorophenyl)-1-piperazinyl]butoxy]-3,4-dihydrocarbostyril, also known as aripiprazole.
Aripiprazole is a compound of the formula (1).
It is a commercially marketed, pharmaceutically active substance useful for treatment of schizophrenia. It is disclosed in EP 367141/U.S. Pat. No. 5,006,528. The commercially marketed product is the free base of the title compound (1).
Solid state aripiprazole was prepared in U.S. Pat. No. 5,006,528 by a two-fold recrystallization of crude aripiprazole from ethanol resulting in colorless flake crystals having a melting point of 139-139.5° C. In an article of Aoki (Study on Crystal Transformation of Aripiprazole, The Fourth Japan-Korea Symposium on Separation Technology, p. 937 ff (1996)), this solid state form was designated as Type I aripiprazole and identified as an anhydrate. Aoki also teaches that the Type I aripiprazole may be converted into a Type II aripiprazole by heating at 130-140° C. for 15 hours. This product is an anhydrate as well with a melting point of 150° C. When both Type I and Type II aripiprazole were recrystallized from an alcoholic solvent containing water up to 20%, the product is an aripiprazole hydrate labeled as Type III by Aoki. Type III aripiprazole can be converted into Type I by heating at 80° C.
WO 03/26659 (EP 1330249) teaches that the Type I aripiprazole, the alleged original solid form of aripiprazole, is significantly hygroscopic. This document also disclosed other crystalline forms of aripiprazole. One form (Form A) is a hydrate, the remaining (Forms B-G) are low hygroscopic anhydrates, differing with arrangement of molecules in the crystalline lattice.
It would be desirable to form crystalline Type II of aripiprazole without the need for a heat treatment or heat conversion. In particular, it would be desirable to find an alternate, economically more advantageous process, which does not require long-term exposure to high temperatures.